Pharmacology

Although many adrenergic drugs have been evaluated for their specificity for a particular receptor subtype, each adrenergic drug used in ophthalmology can occupy several different subreceptors. These receptors appear to differ in different animals. The level of specificity for a given receptor often defines certain clinical characteristics of a drug. Epinephrine is the least selective, activating alpha-1, alpha-2, and beta receptors. Among the alpha-2-selective agonists, brimonidine is the most alpha-2-selective in some animal models. The crossover activation of alpha-1 receptors by clonidine and apraclonidine accounts for their tendency to cause con-junctival blanching, eyelid retraction, and mydriasis. In contrast, brimonidine's more highly specific alpha-2 activation causes miosis, but still has enough residual alpha-1 activation to cause mild conjunctival blanching.

The ability of adrenergic drugs to penetrate the cornea is, in part, directly related to the lipophilicity of the compound. Intact corneal epithelial and endothelial membranes are a formidable barrier for hydrophilic drugs. That is why a 10-fold lower concentration of dipivefrin, 0.1%, the more lipophilic prodrug of epinephrine, can be used with efficacy equal to epinephrine 1%. Unfortunately, the lipo-philic nature of clonidine and brimonidine, which permits rapid corneal penetration, also allows penetration of the blood-brain barrier, where stimulation of central alpha-2 receptors may cause sedation and systemic hypotension. Apraclonidine was made 25% more hydrophilic than clonidine by the addition of an amide group to the benzene ring, virtually eliminating potentially dangerous systemic side effects.14

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